Blood vessel constricting compositions and methods of using same



United States Patent 3,238,101 151.001) VESSEL CUNSTRICTING COMPQSITIONSAND METHODS OF USING SAME Wolfgang ll rnhstorfer and HelmntMiiller-Calgan, Darmstadt, Germany, assignors to E. Merci:Alktiengesellschaft, Darmstadt, Germany No Drawing. Filed Sept. 9, 1964,Ser. No. 395,280 Claims priority, application Germany, Nov. 23, 1960, M47,194 Claims. (Cl. 167-58) The present application is acontinuation-in-part of copending application Serial No. 154,053, filedNovember 21, 1961, now United States Patent No. 3,161,653 dated December15, 1964.

The principal object of this invention is to provide novel imidazolinederivatives and acid addition salts thereof, and a process ofadministering these derivatives to animal life to effect avasoconstricting eifect.

Another object is to provide a novel process for the preparation ofthese derivatives, and to provide intermediate compounds as aconsequence thereof.

Still other objects and advantages will become apparent upon furtherstudy of the specification and appended claims.

The main novel imidazoline derivative of this invention is 2 [(2methyl-benzo-thienyl-3')-methyl]-A -imidazoline, structurallyrepresented by formula I, as follows:

The acid addition salts of the foregoing compound are also included inthis invention, preferably pharmaceutically acceptable acids, such ashydrohalic acids, sulfuric acid, orthophosphoric acid, alkane carboxyacids, such as acetic acid, propionic acid and their higher homologs upto 12 carbon atoms, polybasic acids, such as oxalic acid, tartaric acid,succinic acid, maleic acid, ascorbic acid, citric acid, etc.; sulfonicacids, such as methane sulfonic acid, ethane sulfonic acid, benzenesulfonic acid or p-toluene sulfonic acid, aromatic carboxy acids, suchas benzoic acid, salicylic acid, or p-amino salicylic acid.

These new compounds are vasoconstrictors and cause, when appliedlocally, a rapid and long-lasting constriction of the membranes in thenose and throat areas and on the eye. All tests have proven thesuperiority of these compounds over comparative substances with regardto degree and period of efficiency. In a CNS-screening test on mice, anoral dose of only 300/ug./kg. 2-[(2'-methylbenzo-thienyl-3 -methyl] -A-imidazoline caused enlargement of the lid openings and the hair tostand on end, whereas commercial solutions of xylometazoline hydrochloride and tetrahydrozoline, as well as naphthazoline nitrate, in thesame test, were 3-7 times less efiicient.

Furthermore, the compound according to this invention has twice as mucheffect as compared to the known 2-(naphthyl-1'-methyl)-2-imidazoline,the period of effect being 1.3-1.5 times as long. As compared to the2-(2',6- dimethyl-4'-tert.butyl-benzyl)-2-imidazoline, its effect is 5times greater, the period of effect being the same.

The new compounds may be utilized, on account of its vasoconstrictingeffects, as a medicine for constricting membranes, especially nasalmembranes.

The new compounds can be employed in aqueous solutions of 1:500 to 1:10,000, preferably 112,000 to 114,000 on a parts by weight basis. Forchildren, a concentration of about 114,000 is recommended. For colds, aswell as affected sinus, 24 drops of the compound 1 to 3 times daily areto be inserted into each nostril. Preferably, then, a unit dosage of thevasoconstrictive agent of this I NHCH2 ice invention amounts to 0.025 to0.1 mg. The solutions are to be employed generally for the constrictionof the membranes, being particularly advantageous for diagnosticpurposes, mainly for rhinitis (acute, allergic, vasomotoric), sinusitis,nasopharyngitis, laryngitis, conjunctivitis, and keratitis.

The drops, or spray solutions, prepared for the purpose of constrictinghuman nasal membranes are preferably produced with the addition of abuffer system and a small amount of a bactericide. The buffer systemsare employed to maintain a pH of about 5 to 8; many of these buffersystems are known in the art. As bactericides, any pharmacologicallyacceptable (e.g., non-toxic) bactericidal agents can -be employed, suchas benzalkoniurn chloride, neomycin, bacitracin or chloramphenicol.

Solutions of the following type, for example, can be employed:

Example A 2 [(2 methyl benzo thienyl-3)-methyl-A imidazolinehydrochloride, g 0.5 Sodium borate, g 2.65 Boric acid, g 17.1fi-phenylethylalcohol, g 2.5 Water, ml 1000.0

Example B 2 [(2' methyl benzo-thienyl-3)-rnethyl]-13 imidazolinehydrochloride, g 0.5 Boric acid, g 5.7 Sodium acetate (3H O), g 14.0Tert. trichloro-butanol, g 5.0 Potassium sorbate, g -1 1.0 Water, ml1000.0

Example C 2 (2'-methyl-benzothienyl-3 -methyl] -A -imidazolinehydrochloride (0.25 g.) and 0.2 g. of benzalkonium chloride aredissolved in 700 ml. of distilled water. After adjustment of thesolution to a neutral pH with 0.1 N-sodium hydroxide solution, 10.2 g.of sodium dihydrogen phosphate and 11.1 g. of disodium hydrogenphosphate are added and the solution is made up to 1000 ml. withdistilled water.

Due to its blood-pressure-increasing properties, the new compound canalso be employed as a circulatory drug, for example, for shockconditions. In this case, the compound of Formula I maybe appliedparenterally by injection or permanent drop infusion in sterilized,physiological salt solutions. In these cases, a unit dosage of the drugamounts to 0.01 to 1 mg, the concentration preferably being about 0.2 to1000 mg./ liter.

According to this invention, the new derivative and the acid additionsalts thereof can be produced as follows:

(Z Methyl-benzo-thienyl-3)-acetic acid or one of the functional acidderivatives thereof can be utilized as a reactant material. A compoundof this group can be reacted either with ethylene diamine itself; orwith a N-acyl derivative of ethylene diamine; or with ammonia, orammonia-yielding agents and a compound which can be converted intoethylene diamine by a treatment with arnmonia. The(Z-methyl-benzo-thienyl)-acetic acid is prepared from2-rnethyl-benzo-thiophen (cf. Chemical Abstracts, volume 53, col. 5229,1959) by chloromethylation (reaction with formaldehyde and hydrochloricacid) in a known manner and by reacting the thus obtained2-chloromethyl-benzothiophen with sodium cyanide to form thecorresponding nitrile which may be saponified in the usual way.

It is also possible to utilize, for example, esters, ortho esters, acidchloride, amides, thioamides, amidines, imino ether, thioimino ether,imino halogenides or the nitrile as functional acid derivatives of the(Z-methyl-benzothienyl3)-acetic acid. For this purpose, the reactionconditions may be chosen such that the functional acid derivatives areformed only during the reaction.

Besides ethylene diamine, reactive N-derivatives of the ethylene diaminecan also be employed. Those ethylene diamine derivatives areparticularly suited which, in the course of a reaction with carboxyacids or the functional derivatives thereof, yield imidazolines notsubstituted on the nitrogen atom. Compounds of this nature are forexample N-acyl ethylene diamine, wherein the acyl groups preferablypossess 2-4 carbon atoms; furthermore, N,N-diacyl ethylene diamineswhich may also be of cyclic nature, such as for example ethylene urea orethylene thiourea.

Compounds which are convertible into ethylene diamine by means oftreatment with ammonia are, for example, ethanolamine and the estersthereof, ,G-halogen ethylamines, such as B-chloroethylamine, ethylenedihalogenides, such as l, 2-dichloroethane, or ethylene chlorohydrin.Ethylene diamine or its derivatives can be employed either as free basesor in the form of their monoor disalts. Thus, the ethylene diamine canbe employed for example as the mono-p-toluene sulfonic acid salt.

An acid amide, for example, can act in the same way as ammonia, so that,during the reaction of (Z-methylbenzo-thienyl-3)-acetamide withlbromoethylamine, cyclization to the imidazoline derivative occurs.

If the nitrile of the (2-methyl-benzo-thienyl-3)-acetic acid is utilizedasthe reactant material and is reacted with ethylene diamine or itsderivatives, it is preferable to carry out the reaction in the presenceof hydrogen sulfide or hydrogen sulfide-yielding agents, such as carbondisulfide.

The reaction described may lead either directly or stepwise to theimidazoline derivative of Formula I.

Thus, there are obtained intermediate compounds such as, for example,that represented by Formula Ia, as follows:

wherein" X represents OH, SH, or NH and Y represents H or an acylradical having 1-6 carbon atoms.

From compounds of this nature or their tautomeric forms, thesubstituents X and Y can be separated as XY according to conventionalmethods. For example, water can be separated from a compound of FormulaIa, Wherein X=OH and Y='H by the simple expedient of utilizing calciumoxide as a dehydration agent with good yields of the desired imidazolinederivative of Formula I being thereby formed.

Additionally, an intermediate product can be obtained, corresponding tothat represented by Formula Ib, as follows:

wherein Y represents a substituent replaceable by an amine group,

such as halogen, or an hydroxyl group.

From such compounds or their tautomeric forms, the substituent Y can beseparated in the form of HY, forming an imidazoline ring. Intermediateproducts of this type are somewhat unstable compounds, which convert tothe desired imidazoline compound of Formula I when boiled in an inertsolvent, thereby separating HY. The separation reaction proceeds verysmoothly when Y is halogen. The reaction also yields good results whenY=OH and the operation is conducted under dehydrating conditions.

In the course of the stepwise formation of the imidazoline derivative ofFormula I, there can be obtained, as a further intermediate product,compounds of Formula 10, as follows:

wherein Y and Y represent the same or different substituents replaceable'by an amine group, said substituents being like those described inFormula Ib.

If a compound of this type or the tautomeric form thereof is treatedwith ammonia or ammonia-yielding agents, the imidazoline derivative ofFormula I is obained. The reaction procedure is very smooth when Y and Y=halogen, especially chlorine.

Funther in accordance with this invention, the imidazoline derivative ofFormula I can also be obtained by the isomerization of a compound ofFormula H or III, as follows:

X represents OR or a halogen, and

R represents H, an acyl group having 1-6 carbon atoms, or a loweraliphatic hydrocarbon having 1-6 carbon atoms.

wherein The irnidazoline derivative is made by separating thesubstituent X as HX. If X equals halogen, the separating process iscarried out under the conventional conditions of a halogen hydrogenseparation, for example by treatment with collidine or pyridine. In caseX equals hydroxyl, the separation is accomplished by treatment with aconventional dehydration agent. If R is an aromatic or higher aliphaticacyl group, for example the benzoyl radical, it is possible to introducethe 1,2-double bond into the heterocyclic portion by merely heating,while benzoic acid is separated.

Depending on the method used, the new imidazoline derivative is obtainedas a free base or in the form of one of its acid addition salts. Fromthe free base, various acid addition salts can be prepared by treatmentwith acids according to known methods. For the production of such salts,those acids are preferred which are pharmaceutically acceptable acids,such as hydrohalic acids, sulfuric acid, orthophosphoric acid, alkanecanboxy acids such as acetic acid, propionic acid and their higherhomologs up to 12 carbon atoms, polybasic acids, such as oxalic acid,tartaric acid, succinic acid, maleic acid, ascorbic acid, critric acid,etc.; sulfonic acids, such as methane sulfonic acid, ethane sulfonicacid, benzene sulfonic acid or p-toluene sulfonic acid, aromatic carboxyacids, such as benzoic acid, salicylic acid or p-amino salicylic acid.

To further illustrate the processes which can be employed to manufacturethe novel compounds of this invention, the following examples arepreferred specific embodiments thereof, but are not to be considered aslimitat-ive of the specification and appended claims.

Example 1 9.35 g. of (2-methyl-benzo-thienyl-3)-acetonitrile (preparedby chloro'methylating 2-ethyl-benzo-thiophene and reacting thechloromethyl derivative with NaCN, and crystallizing from petroleumether, crystals melting at 78 C.) and 11.6 g. of ethylenediamine-mono-p-toluene sulfonate are mixed and heated in an oil bath to225-230 C. for one to 1% hours, and NH is thereby separated. After beingcooled, the reaction mixture is treated with approximately 50 ml. of anapproximately aqueous NaOH solution. The base precipitated thereby isvacuum filtered, dried, and recrystallized from cyclohexane orcyclohexane petroleum ether. 7.5 g. of 2-[(2-methylbenzo-thienyl-3')methyH-M-imidazoline corresponding to 65% of the theoretical yield areobtained, which compound, after repeated recrystallization, melts at 156157 C.

By dissolving the free base in ethanolic hydrochloric acid and mixingwith ether, the crystalline hydrochloride can be obtained in the usualmanner, which hydrochloride melts, when recrystallized from alcoholether, at 248250 C. If methane sulfonic acid is utilized instead ofhydrochloric acid, the corresponding methane sulfomate is obtained.

Example 2 9.35 g. of (2-methyl-benzo-thienyl-3)-acetonitrile, 3.2 g. ofapproximately 95% acetylene diamine, and 0.25 ml. of carbondisulfide aremixed and heated to approximately 100 C. for 48 hours. After beingcooled, the raw product is recrystallized from cyclohexane, wherebythere is obtained 2-[(2-methyl-benzo-thienyl-3)-methyl]- A -imidazoline,M.P. 155 C.

Example 3 10.3 g. of (2-methyl benzo-thienyl-3)-acetic acid and 11.6 g.of ethylene diamine-mono-p-toluene sul fonate are heated to 220250 C. inan oil bath for 23 hours. After being cooled, the residue is processedaccording to Example 1, and 2-[(2'-methyl-benzo-thienyl-3')-methyl]- A-imidazoline of M.P. 155-157 C. is obtained.

Example 4 4.7 g. of ethylene diamine are added slowly and under icecooling, to 0.05 mol (2-rnethyl-benzo-thienyl-3)-acetyl chloride(produced from 10.3 g. of (Z-methyl-benzothienyl-3)-acetic acid and 10ml. of thionyl chloride). After the completed reaction, it is slowlyheated to a bath temperature of 200220 C. and the reaction mixture iskept at that temperature for about 2 hours. The mixture is cooled, theresidue is treated With approximately 50 ml. of 10% aqueous sodiumhydroxide and the base is extracted twice with 30 ml. of aliquotchloroform. After the chloroform is evaporated, the base is dissolved in40 ml. of 10% hydrochloric acid and the neutral substances are removedby means of ether extraction. By adding an excess of 10% sodiumhydroxide solution to the acidic, aqueous extract,2-[(2'-methyl-benzo-thienyl- 3')-methyl]-A -imidazoline is obtainedwhich, after being vacuum filtered and dried, is recrystallized fromcyclohexane or cyclohexane petroleum, M.P. 153-155 C.

Example 5 10.25 g. of (2-methyl-benzo-thienyl-3)-acetamide and 11.6 g.of ethylene diamine-mono-p-toluene sulfonate are heated to 200210 C. inan oil bath for 3 hours. After proceeding according to Example 1, thereare obtained 6.8 g. of 2 [(2' methyl benzo-thienyl-B)-methyl]-Aimidazoline which melts at l55-157 C. after recrystallization fromcyclohexane.

Example 6 9.35 g. of (2-methyl-benzo-thienyl-3)-aceto-nitrile and 7.2 g.of N,N'-diacetyl ethylene diamine are heated to 240 C. in an oil bathfor 3 hours. After being cooled, the dark raw product is processedaccording to Example 4, and 2 [(2' methyl benzo thieny1-3)-methyl]-Aimidazoline is obtained which melts at 152-155 C. after severalrecrystallizations.

Example 7 9.35 g. of (2-methyl-benzo-thienyl-3)-aceto-nitrile and 5.1 g.of rnercapto irnidazoline are heated to 250 C. in an oil bath for 3hours. After proceeding according to Example 4, and after severalrecrystallizations from cyclohexane petroleum ether, there are obtained2-[ (2-rnethylbenzo thienyl 3') methyl] A -imidazoline, M.P. 152- 15 5C.

Example 8 0.05 mol of raw (2-methyl-benzo-thienyl-3)-acetimino ethylether hydrochloride (produced from 9.35 g. of (2-methyl-benzo-thienyl-3)-acetonitrile) and the calculated amount ofethanol and anhydrous hydrogen chloride are introduced into a solutionof 4.0 g. of ethylene diamine monohydrate in 40 ml. of absolute alcoholand boiled under reflux for 4 hours. The alcohol is then distilled off,the residue is treated with approximately ml. of approximately 10%sodium hydroxide solution and processed according to Example 4. The2-[(2-methylbenzo-thienyl-3')-methyl]-A -imidazoline obtained therebymelts, after recrystallization, at 152155 C.

Example 9 10.25 g. of (2-methyl-benzo-thienyl-3)-acetamide and 10.25 g.B-bromoethyl-amine hydrobromide are heated to approximately 220230 C. inan oil bath for 3 hours. The residue is processed as set forth inExample 4, and 2 (2'-methyl-benzo-thienyl-3' -methyl] -A -imidazoline isobtained which melts, after recrystallization from cyclohexane petroleumether, at 152155 C.

Example 10 10.25 g. of (2-methyl-benzo-thienyl-3)-acetamide and 10.3 g.of 1,2-dibromoethane are mixed with 10 g. of liquid NH in an autoclaveand agitated at 200250 C. for 4 hours. After cooling, the excess ammoniagas is released, and the residue is processed as set forth in Example 4,and there is obtained 2-[(2'-methyl-benzothienyl-3')-methyl]-A-imidazoline which melts at 151- 153 C. after recrystallization.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions. Consequently, such changes and modifications are properly,equitably and intended to be within the full range of equivalence of thefollowing claims.

What is claimed is:

1. A process for constricting blood vessels in animals, which processcomprises administering to said animals an effective but non-toxicamount of a compound selected from the group consisting of2-[(2'-methyl-benzo-thienyl- 3)-methyl]-A -imidaZoline and thepharmaceutically acceptable acid addition salts thereof.

2. A process of administering the imidazoline derivatives of claim 1 tomammals to efiect a vaso-constricting action.

3. A therapeutic solution comprising an aqueous solution of animidazolinc derivative selected from the group consisting of 2 [(2'methyl benzo thienyl-3')- methyl]-A -imidazoline and thepharmaceutically acceptable acid addition salts thereof, theconcentration of said derivative being about 1:2,000 to 114,000.

4. A therapeutic solution comprising an aqueous solution of animidazoline derivative selected from the group consisting of 2 [(2'methyl benzo thienyl-3)- methyl]-A -imidazoline and the pharmaceuticallyacceptable acid addition salts thereof, the concentration of saidderivative being about 1:500 to 1:10,000.

5. A pharmaceutical composition in unit dosage form, comprising apharmaceutically acceptable carrier and 0.025 to 0.1 mg. of animidazoline derivative selected from the group consisting of2-[(2'-methyl-benzo-thienyl-3')- methyH-N-imidazoline and thepharmaccutically acceptable acid addition salts thereof.

References Cited by the Examiner UNITED STATES PATENTS 2,441,867 5/1948Carlson 260 309.6 2,457,047 12/1948 Kyrides 260309.6 2,744,909 5/1956Spceter 260--309.6 2,780,577 2/1957 Phillips 167 2,955,073 10/1960 DeBeer 167 65 2,965,648 12/1960 Wiegand et al. 260309.6 2,995,564 8/1961Duennenberger 260 309.2 3,010,972 11/1961 Kaiser 260 330.5 3,024,2483/1962 Werner 260330.5 3,042,674 7/1962 Faust 260309.6

OTHER REFERENCES Blicke et al.: J. Am. Chem. Soc., vol. 70, pp. 376870,1948.

Scholz: Ind. and Eng. Chem, vol. 37, pp. -125, 1945.

JULIAN S. LEVITT, Primary Examiner.

1. A PROCESS FOR CONSTRICTING BLOOD VESSELS IN ANIMALS, WHICH PROCESSCOMPRISES ADMINISTERING TO SAID ANIMALS AN EFFECTIVE BUT NON-TOXICAMOUNT OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF2-((2''-METHYL-BENXO-THIENYL3'')-METHYL)$2-IMIDAZOLINE AND THEPHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF.